Advances in the Management of Multiple Sclerosis: A closer look at novel therapies. Disclosures

Transcription

1 Advances in the Management of Multiple Sclerosis: A closer look at novel therapies Lily Jung Henson, MD, MMM, FAAN Chief of Neurology Piedmont Healthcare, Atlanta, GA National Association of Managed Care Physicians Fall Managed Care Forum November 13, 2015 Disclosures National MS Society National Board member Fast Forward Board of Managers member American Academy of Neurology BrainPAC chair Research funding from Biogen, Novartis, Genzyme, Tcelna, NIH Speaker s bureau for Teva, Novartis, Pfizer, Serono, Genzyme Consulting fees from Biomarin 1

2 Objectives Discuss current MS therapies and pathway for drug selection Discuss safety concerns of MS therapies Discuss NEDA (no evidence of disease activity) Discuss emerging MS therapies and their impact on efficacy and safety Current disease modifying therapies 2

3 MS Disease Modifying Therapies Betaseron (interferon beta 1b sq qod) 1993 Avonex (interferon beta 1a IM qweek) 1996 Copaxone (20 mg/ml glatiramer sq qd) 1996 Novantrone (mitoxantrone IV q3 months) 2000 Rebif (interferon beta 1a sq tiw) 2002 Extavia (interferon beta 1b sq qod) 2009 Tysabri (natalizumab IV qmonth) 2004 Gilenya (fingolimod po daily) 2010 Aubagio (teriflunomide po daily) 2012 Tecfidera (dimethyl fumarate po bid) 2013 Copaxone (40 mg/ml sq tiw) 2014 Plegridy (pegylated interferon beta 1a sq q2 weeks) 2014 Lemtrada (alemtuzumab 5 days IV, then 3 days IV after 12 months) 2014 Glatopa (generic glatiramer 20 mg/ml sq qd) 2015 How to make sense of it? injectables orals infusions Route of administration is NOT the answer! 3

4 Severity of Disease Standard course Aggressive course Able to use injectables JCV ab yes no + Depression and/or liver disease yes no Orals Gilenya (if no cardiovascular risk) Aubagio (if no liver disease) Tecfidera JCV ab index Tysabri Glatiramer Interferons >0.9 <0.9 2years Reassess disease activity at 6 months Lemtrada Quiet Active Continue DMT and reassess annually unless new symptoms Assess compliance and/or side effects no yes Aggressive course algorithm Switch to alternative therapy Don t forget the other two prongs of MS management Treatment of acute relapses 1 gm. IV methylprednisolone x 3 to 5 days Acthar gel 80 to 120 u daily IM/SQ x 2 3 weeks (intolerant of high dose steroids, steroid failure, poor IV access or preference for self injection) Symptomatic treatment Fatigue Bladder dysfunction Cognitive dysfunction Bowel dysfunction Pain Sexual dysfunction Dysesthesias Ambulatory dysfunction Spasticity 4

5 symptomatic management always has been and continues to be the bedrock of patient care in MS as symptoms impact quality of life for patients prescribers must retain the right to decide on the best treatment for each individual patient. The varied and individualized course of MS mandates full access to symptomatic management as well as disease modifying therapies which, in the best judgment of the prescriber, offer optimal treatment outcomes. Medications to treat symptoms are carefully decided on an individual basis and by best practice regimens. Lack of understanding of the disease course and the challenges of MS treatment result in poor decision making practices by the insurance plans and specialty pharmacies and subsequent denial of prescribed medications. This leads to an inability to adequately serve the people living with MS, negatively affecting the patient s quality of life. New safety data on current therapies 5

6 Natalizumab and Progressive Multifocal Leukoencephalopathy 588 cases of PML as of September 2015 (585 MS, 3 Crohn s) 142,000 patients received natalizumab post marketing as of June 2015 Global overall incidence is 4.03/1000 patients 77% alive with varying levels of disability; 23% died Duration of therapy prior to diagnosis range from 8 to 110 doses 86% with > 24 doses at time of diagnosis Biogen communication, September Natalizumab and PML Factors that increase risk of PML: Longer treatment duration (> 2 years) Prior treatment with immunosuppressant (e.g. mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate) + JCV antibody Biogen communication, September

7 Global cumulative natalizumab PML risk estimates by treatment duration 3.94 Biogen communication, September 2015 Management of PML risk in natalizumab patients Clinical vigilance is key Improved survival associated with Early diagnosis Younger age at diagnosis Less functional disability prior to diagnosis Lower JC viral load at diagnosis More localized brain involvement by MRI at time of diagnosis 7

8 Anti JCV antibody testing JCV infection required for PML Anti JCV ab status is not diagnostic of PML Anti JCV ab negative = exposure to JCV not detected; lower risk of PML than those who are JCV ab +; potential for new JCV infection or false negative test rate of JCV ab seroconversion is 3 8% annually Don t do < 2 weeks after plasma exchange ~99% sensitive Biogen communication, September yo with MS, dx ed 1996, treated with GA, received 4.5 years of DMF 240 mg tid in open label extension of DEFINE Developed severe lymphocytopenia ( cells/cu mm) after 12 months, persisted for 3.5 years Developed severe gait, speech and left UE difficulties in Aug 2014, treated with steroids, plasmapheresis for presumed relapse Diagnosis made based on MRI and CSF JCV DNA PCR in October

9 Pre PML Onset of symptoms PML diagnosed PML associated with fumaric acid esters used for psoriasis Dammeier described a patient with lymphocyte counts between /microL for prolonged time periods Nieuwkamp described a patient with delayed release DMF with nadir of 792 cells/mm 3 Severe lymphopenia not required; alteration of immune surveillance for prolonged time is critical for development of PML ECTRIMS 2015, P642 Nieuwkamp DJ, et al. N Engl J Med. 2015:

10 Management of patients on tecfidera suspected of PML Check CBC before initiating therapy Hold Tecfidera for signs and symptoms suggestive of PML Follow CBC every 6 months Hold Tecfidera for lymphocyte counts < 500 > 6 months and follow until lymphopenia resolves Biogen communication PML associated with Gilenya > 18,000 patients received Gilenya after Tysabri use (~15 to 20%) as of April cases of PML as of August with prior history of Tysabri use, 5 with MRI evidence before first dose of Gilenya 3 without Novartis communication 10

11 Estimated PML Risk Novartis communication 11

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16 NEDA No evidence of disease activity no relapse no worsening of EDSS lack of new/enlarging T2 lesions on MRI lack of gadolinium enhancing lesions on MRI 16

17 Criteria for NEDA to consider treatment adjustment MRI parameters Multiple new or enlarged T2 lesions or gad enhancing lesions Relapse activity > 1 relapse with incomplete remission > 1 severe relapse with necessity of escalating acute therapy (2 gm. IV solumedrol x 5 days) > 2 objective relapses without residual symptoms at 1 year Disability progression EDSS < 3 fatigue and cognitive parameters are not considered enough Gold R., Hartung H., Stangel M., Wiendl H., Zipp F., Expertenmeetings T. (2012) Therapeutic goals of baseline and escalation therapy for relapsing remitting multiple sclerosis. Akt Neurol 39: Emerging therapies in MS 17

18 Daclizumab high yield process (DAC HYP) Humanized monoclonal antibody binds to CD25 (alpha subunit of interleukin 2 receptor) Reversibly modulates IL 2 signaling, reducing pro inflammatory activated T cells, expands immunoregulatory CD56 bright NK cells DECIDE Randomized double blind, active controlled phase 3 study 1841 RRMS patients, over 144 weeks DAC HYP 150 mg SQ q 4 weeks vs.. interferon beta 1a 30 mcg IM q week 18

19 DECIDE results ARR 0.22 vs. 0.39; 45% lower, p<0.001 T2 lesions 4.3 vs. 9.4; 54% lower, p<0.001 at 96 weeks Disability progression at 12 weeks at 16% vs. 20%, p=0.16 Serious adverse events 15% vs. 10% infections, rash, eczema, elevations in ALT Kappos et al. NEJM Oct 8;373(15):

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25 ORATORIO Ocrelizumab in PPMS placebo controlled double blind phase III study OCR 300 mg IV given 14 days apart every 24 weeks x 120 weeks 732 patients, 183 sites Mean age at baseline was 44.6 years 49.3% females, 94.1% were white Mean baseline EDSS score was 4.70; mean duration since MS symptom onset 6.48 years; mean duration since PPMS diagnosis was 2.82 years. Number of patients untreated with any MS medication in the prior 2 years was 656 (89.6%) At baseline, 26.4% of patients had gadolinium enhancing (Gd+) T1 lesions; mean number of Gd+ T1 lesions was 1.0; median volume of T2 lesions was 6.96 cm3; and mean normalized brain volume was cm3 on MRI X. Montalban et al. ECTRIMS Late breaking news. 25

26 ORATORIO results Primary endpoint significant reduction in 12 week confirmed disability progression (24%), p= Secondary endpoint Significant reduction in 24 week confirmed disability progression (25%), p=0.0365; significant reduction (29%) in progression rate of walking time, p= Significant reduction in T2 lesion volume at 120 weeks ( 3.4% vs.. 7.4%, p<0.0001) Significant reduction in rate of whole brain volume loss (17.5%, p=0.0206) X. Montalban et al. ECTRIMS Late breaking news. Adverse events Similar to placebo Most common were mild moderate infusionrelated reactions Infusion reaction most severe with initial dose, then tapers X. Montalban et al. ECTRIMS Late breaking news. 26

27 ECTRIMS 2015 Thank you for your attention! Questions??? 27